Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells

To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) leading to acute aortic dissection, we used single-cell RNA sequencing to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result,MFSmod were identified only in the aorta of Fbn1mgR/mgR mice. In situ hybridizations of diagnostic transcripts located MFSmod cells to the intima of Fbn1mgR/mgR aortas. Consistent with angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients. Hypomorphic Fbn1mgR/mgR mice were routinely backcrossed for 10 generation on the C57BL/6J background. Mutant mice and WT littermates were euthanized to harvest aortic specimens spanning from immediately above the aortic root to immediately before the brachiocephalic artery.Aortic tissues of each genotype and treatment were pooled together, cleaned, minced and digested to make single-cell suspensions, then immediately processed according to manufacturer’s instructions.